Triterpenoid acid derivatives and compounds produced therefrom



3 its 957 TRITERPENOID A0115 DERIVATIVES AND COM- POUNDS raonucnn THEREFROM Josef Fried, Princeton, and Gerald W. Krakowr,Elma-.

heth, NJ., assignors to Olin Mathieson Chemical Corporation, New York, N.Y., a corporation of Virginia N Drawing. Filed May 29, 1962, Ser. -No. 193,425 26 Claims. (Cl. 260-2395) This invention relates to and has as its objects the provision of new physiological active steroids, methods for preparing the same, and new intermediates useful in said preparation.

The final products of this invention can be represented by the formulae:

M. Mp3s and wherein Z is selected from the group consisting of hydrogen, hydroxy, 0x0 (0:), acyloxy'and alkanoyl; R may be the same or diiferent and is selected from the group consisting of hydrogen, hydroXy and acyloxy, and together R may be oxo (O: and R may be the same or different and is selected from the group consisting of hydrogen, hydroxy, oxo (0:), and acyloxy. application and the claims appended hereto, a curved line [i] is employed in the linkage of atoms in a formula, it is meant to denote that the connected atom may be either in the alpha or beta position as is determined in the respective compounds.) t

The preferred acryloxy radicals are those of hydrocarbon carboxylic acids of less than twelve carbon atoms, as exemplified by the lower allcanoic acids (e.g., acetic, propionic butyric and tert-pentanoic acids), the lower alkenoic acids, the monocyclic aryl carboxylic acids (e.-g.,'

benzoic and toluic acids), the monocyclic aryl lower alkanoic acids (e.g., phenacetic and 3-pheny1propionic acids);

the cycloalkane carboxylic acids and the cycloalkene oarboxylic acids.

The alkanoyl groups preferably employed in the practice of this invention may be either straight or branched (Whenever, in this chain and are those having less than ten carbon atoms, for

- example, hexanoyl, pentanoyl, heptanoyl, lower alkylfialkanoyl, such as methyl-'hexanoyl, o di-lower' alkyl-alkanoyl, such as dimethylhexanoyl. j

5 The compoundsof this invention are physiologically active steroids which possess protein-anabolic activity and which may be used in place of such known proteineanaboh ic steroids as 17-ethyl-l7-nortestosterone in the treatment of post-operative shock and other conditions where tissue degeneration has occurred. Administration of the prodnets of this invention maybe accomplished either peror- I ally of parentenally, in the same manner as 17-ethyl-l9- nortestosterone, for example, the dosageand/or concentration being adjusted for the relative potency of the particular steroid. In addition, compounds of this invention are physiologically active steroids which possess androgenie activity and may be used in place of such known androgenicallyactive steroids as testosterone in the treatment of eunuchoidism being formulated for such admin- 20 istration in the same manner and/or dosage as testosterone. It has also been found that compounds of this invention are physiologically active steroids which possess antiandrogenic activity, i.e., they inhibit the action of androgens, and they can'be used in the treatment of 'such conditions as hyperandrogenic acne. The compounds may be formulated for such administration, theconcentration:

and/ or dosage being based on the activity of the particular compound and the requirements of the patient.

The final products of this invention are prepared by the, process of this invention which entails anumber of steps beginning with a triterpenoid acid as a starting material. By a triterpenoid acid, it is here meant a polymethylsteroid having a D-ring structure represented by the formula vas RR V g R wherein R may be the same or different and may be either hydrogen or lower alkyl and R may be the same or difi'erent and may be selected from the group consistingof hydrogen and hydroxy. Examples of the .triterpenoid acids which may be employed in the practice of this invention include eburicoic, polyporenic, tumulosic, pinicolic,

elemolic, elemonic, dehydroeburicoiq dehydroelemolic, dehydtoelemonic and other'l-ike acids. The steps of the process (employing eburicoic acid as'the starting material) are shown by the following equations wherein R, R and R are the same or ditferent and represent hydrogen, lower alkyl, acyl and together with the oxygen atom to which I ,they are joined may represent 0x0 (O=):

mmott Acid 1 In the first step'of the process of this invention, eburicoic acid is converted to its 3-ester derivative (Compounds A). The 3-acetate ,ofeburicoic acid is a known compound. Other 3-esters can be prepared in the usual manner by reacting eburicoic acid with the desired acylating (e. g., acyl chloride oracid anhydride) in the presence of a base,

the preferred esters arelthose with hydrocarbon carboxylic acids of less than twelve carbon atoms. These are formed by reacting with the-.acyl chloride or acid anhydride of a hydrocarbon carboitylic acid of less thantwelve carbon atoms, such as one of the acids listed hereinbefore.

' The. 3-ester is then converted to a corresponding ester of M-eburiceneQl-oic acid (Compounds B). This may .be :accornplished'bythe hydrogenation of the, 3-ester in the presence of a hydrogenation catalyst, for example, palladium on charcoal, wherebyCompounds B :are obtained directly. Alternatively, Compounds B maybe x R =Cfi 3 jgvmgacmc 0M i m methane the S-acetate esters (Compounds A) in ether to xrglg mnf omx r I 5 flQiB The methylated acetate ester (Compounds A) is then 'B').- Y i a 7 Compounds "3 are then oxidized as by treatment with pounds C(Wherein R is hydrogen), Compounds C may a basic medium; such as collidine, at elevated temperatures. 4 l

Compounds C'are thenreduoed'as by treatment with zinc in glacial acetic acid preferably at elevated ltemperaturestoproduce the eburicane-fLlI- diones (Compounds such as collidine at eleyated temperatures such as pyridine, Although any ester can be prepared,

producedby first methylating'as by reacting with diazo-,

5 produce the methylated S-acetate'ester of ebnricoic acidil treated with hydrogen in the presence of a hydrogenation catalyst to produce the A -eburicene-esters (Compounds an'oxidizing agent, for example,'chromic acid in an acetic acid medium3 to produce 5 the A -eburicene-7,1l-diones (CompoundsC). To obtain the 21-oic acids} of Combedem'ethylated as by treatment with a lithium halide in.-

' D). ,Inordertoobtain' the 21-oi'c' acids ocf Compounds'D- I (wherein R- is hydrogen) Compounds Dare demethylated :as by treatment with a lithiumhalidein a basic medium,

75 ComP Unds Dare then converted to the ll-keto-eb'uri came (Compounds F) by treatment first with an alkylenedithiol, e.g., ethane-dithiol, in the presence of a Lewis :acid, such as, borontrifluoride etherate to produce thev dithioethylene ketals (Compounds E), which are new compounds of this invention. Compounds B may then be treated at elevated temperatures with a sponge nickel catalyst in an organic solvent (e.g., ethanol), to produce Compounds F, which are also new compounds of this invention.

Alternatively, Compounds F may be obtained by treating Compounds D with hydrazine and a base, such as potassium hydroxide, at elevated temperature. In addition to the reduction of the 7-keto group, there occurs hydrolysis of the ester groups at C and C and the latter are reformed by treatment first with an acyl-ating agent (i.e., acid 'anhydride or acyl chloride) in the presence of a base (e.g., pyridine) followed by treatment with a methylating agent (e.g., ethereal diazomethane), to produce Compounds F directly.

In order to obtain the 2l-oic acids of Compounds F (wherein R is hydrogen) Compounds F are demethylated as by treatment with a lithium halide in a basic medium, such as collidine, at elevated temperatures. The eburicane 21-oic acids, Compounds F (wherein R is hydrogen), are then treated with an acid halide (e.g., thionyl chloride or thionyl bromide) to produce the eburicane-Zl-oyl chlorides (Compounds G). These are also new compounds of this invention.

Compounds G are then reduced as by treatment with hydrogen in the presence of a palladium catalyst at an elevated temperature to yield the eburicane-Z-l-al-ll-ones (Compounds H), which are new compounds of this invention.

Compounds H are then treated with a secondary amine, such as pyrrolidine, at an elevated temperature, with or without a strong acid, such as p-toluenesulfonic acid, to produce the 21 (N-substituted)-A -eburicene-1l-ones (Compounds J), such as 21-(N-pyrro1idyl)-A -eburicenell-one, which are also new compounds of this invention.

Similarly, additional 21 (N-substituted)-A -eburicenes (Compounds I) may be obtained by substituting other secondary amines for the'pyrrolidine employed above. Examples of such secondary amines are morpholine and piperidine, which when employed in the practice of this invention, yield respectively 21-(N-morpholyl)-A -eburicene-ll-one, and 21-(N-piperidyl)-A -eburicene-1l-one (Compounds I) which are also new compounds of this invention. I

Compounds I may then be ozonized with. an excess of ozone at reduced temperatures. The ozonide formed is then reduced, as by treatment with Zinc and acetic acid,

to yield the 21-nor-eburicane-11,20-dionesv (Compounds K), which are also new compounds of this invention.

The final products of this invention are obtained by treating Compounds K with a peracid, such as trifiuoroperacetic acid which yields the 3-acetate-17(4,5 dimethylhexanoate) of 4,4,14-trimethyl androstane (Compounds L), which are new compounds of thisinvention.

When in the practice of this invention, the acyl ester compounds (Compounds L) are obtained, the ester can be saponified; in the usual manner, as by treatment with a base, such as potassium hydroxide, to yield the correspondingfree hydroxy derivative and the free hydroxy compounds oxidized to the corresponding keto derivative in the usual manner as by treatment with chromium trioxide to yield Compounds M, which are new final products of this invention. Additionally, subsequent reduction of the final compounds, such as by treatment with lithium borohydride, results in the production of additional new final products of this invention (Compounds M).

In addition to the foregoing process, further steps may be employed to obtain further products of this invention. The basic starting material is the same triterpenoid acid employed in the hereinbefore disclosed process, which starting material is the source of the reactant employed in obtaining the additional products of this invention. The following equations represent the process whereby additional products are obtained; wherein R, R and R" are as hereinbefore defined:

CH2 O I I XXXVI a: cmco R CH3 XXXVII R onaoo R 0H8 Xnr a ornco 513.":

' as zinc and aceticacid, to,v yield the lanostane-7,l1',24-,- triones (Compounds P), which are new compounds of this Q steps set forth hereinbefore in the treatment of Compounds.

' t s r r through M, "thus yielding the ll-keto androstane derival a a l a tives (Compounds .U) which'are alsonew final products of this invention. j OR, 7 additional method of producing the final products of j 5 thISlHVEIIUOIImVOIVES the employment of the derivatives 7 l t f t of Compounds B, as starting material. The different steps be represented by the following equations,wherein R, R

ofthe process and the compounds obtained therefrom can l v and R" are as. hereinbeforedescribed.

r p 10 V Y l 1 no I no 'won" t l I V 1 V N R'OOC In the first step of the subsequent process, Compounds A, obtained, as described hereinbefore, are oxidized, as i with chromicacid in an acid medium, to yield theiA lanoStenc-7,l1,24-triones (Compounds 0) directly. A1- ternatively, Compounds 0 may be obtained by a,twostep; process" byfir'st ozonizing Compounds A, reducing the ozonides formed, as by treatment with hydrogen in r the presence of a hydrogenation catalyst, such 'as'pall-adiumon charcoal to obtain Compounds N. Compounds l N are then oxidized, as bytreatment with chromicacid in acetic acid, to yield CompoundsO. I

Compounds 0 are treated with' a reducing agent, such invention. 7 I a Compounds P are then reacted with an alkylene dithiol, such asx'ethanedithiol, in the presenceofvta Lewis acid,. such as boron trifluoride-etherate catalyst under mild conditions, to yield the dithioethylene ketals (Compounds R) which are new compounds of this invention. "Compounds R are then desulfurized as by heating at elevateditemperatures in "an organic= so1vent, in" the presence of a nickel catalyst, thus yielding the lanostane-Zll-diones I (Compounds T)'which arenew compounds of this invention. a

' CompoundsT may then-be processed'according to the:

A B through M, inorder to, obtain the final derivatives: of '7 products of this invention; 1

Compounds R,'which are Compounds V and are also new Alternatively, Compounds 1 may be treated withan alkylene dithiolsinthepresehce of-a borontrifluoride- V etherate over an extended period-of time at room tempera-, 'z 1,

ture to yield the bis-dithioethyleneketali .(CompoundsiQ) a t a I v whichare newlco-rnpounds of this inventions Refluxing i n' icg co fi 7 C {II- RzncHgcov; 3) 5' the bisdithiolethylene ketals'(Compounds Q) in an ora di inethygfexandylli LvlX Rz'zfi ntasganic solvent in' the presence of a nickelicatalyst yields the IaHOStaHQ-I1 OIXCS (Compounds 8). 1 r L .diglethyl hexanoyl) f Compounds S mayaIsobeobtained directly lay-treating 7 i V is t g p x' 1 O:

Compounds:P, at ;an elevated temperature,with a base g 11 g 1 f R": (4,5d1nieth 1 and reacetylating the compound formed,.' as by treatment 7 v R": 7, 1

.with acetic anhydridezin a ltertiary base,v"and,then rej n LXII :O:

methylating, by ltreatm'entethereal gdiaz'ome thane,

to obtaincompounds S directly. LXIY'R:R':RL:H 7 I Compounds S are treated ,accordin gto the'procedures set forth ,hereinbefore in thet itreatment of Compounds F ,To obtain additionalffinal productsofthisinventioh, is f YII The first step in this additional processing is the treatment of Compounds B with an oxidizing agent, such as, chromic acid and acetic acid, to produce the A -eburicene- 7-ones (Compounds W). CompoundstW are then reduced; as by treatment with lithium and ammonia to produce the eburicane-7-ones (Compounds Y), which are new compounds of this invention; Compounds Y may then be demethylated as by treatment with a lithium halide in a basic medium, such as collidine, at elevated temperatures to produce the eburicane-7-one-21-acids (Compounds X) which are also new compounds of this invention.

To obtain additional final products of this invention, Compounds X are treated in accordance with the procedures 'set forth hereinbefore in the processing of Compounds Ethrough M. Such treatment of Compounds X results in the production of the 7-keto-androstane deriva-' tives (Compounds AA) which arenew final products of this invention. 7

Still other final products of this invention may be obtained by treating Compounds Y in accordance with the Compounds Dthrough M. Thus, Compounds Y are first 7 treated with an alkylenedithiol in the presence of aLeWis ucts of this invention (Compounds 2).

Additional final products of this invention areobtained by-the subsequent processing of the derivatives of Compounds B (wherein R is hydrogen), obtained as set forth hereiubefore. The difierent steps of the process and the compounds obtained therefrom may-be represented by'the following equations wherein R andR are as he'reinbefore defined: a I v LXXIII R:

CHsCO LXXIV R H LXXV RO :O=

In the first step 'of'the process yielding additional final i products Sf-this invention, Compounds B (wherein R acid to produce the 7-dithioethylene ketals (Compounds Y') which compounds are then desulfurizedto produce ishydrogen) are treated with a halogenating agent, such t dihydroeburicoyl chloride (Compound BB),

Compound BB is then treated in accordanc'e with, the procedures setforth hereinb'efore in the processing of h Compounds F t IQl gh' K-to obtain the Af 2l-nor-eburicanes (Compounds; CC) whichare additional new final compounds of this invention; a

Still further additional final products of this invention may be obtained by the processing of the derivatives of Compounds F or Compounds S (whereinR is hydrogen), obtained as set fort-hhereinbefore. vThe additional products are obtained by the process represented-by the following equationswherein R, R and R" are the same as lithium borohydride in tetrahydrofuran to produce thelleompoundsof this invention. the proceduresset forth above for obtaining Conipounds iG through thus yie1ding-i,t11e A -'21-nor-lanostenes (Compounds FF), whieh arenew a V R and R 'fa're as hereinbefore definedz a 4- v V 3 Ti defined hereinbefore; and R' may be hydrogen or lower alkyl:

v I 35 g In the first step of the proeess yielding these additional final produets, Compounds F or sftwherein R is hydro- I gen), obtained asset forth 'hereinbefo're, are treated with."

hydroxy-lanostanes (Compounds EDD compounds of thisinvention: 7 Compounds DD are then treate which ate new r before:

i 'nietha eSuEonyI 1 V RO-C LXXXIV IR CHBCO R 4,5-dimethyl Compounds. and D (wherein-Rf is hydrogen) are. '4 processed according'to the proceduresset'torth herein.-

befote in the production of compounds Go through, M5?

thus yielding as new additional final p roductsof.this in-' vention the7,'1l-diketo-n -androstenes (-Compounds;,GG) and the 7,11-diketo-androstane s.(Compounds HH).:

acid may likewise be obtained when another .triterpenoid acid'is substituted. as the starting material." Thus, :when tumulosic acidis tre'ated'in: accordance with thepro'cedures, set forth'above in obtaining CompoundsA through} the results represented'by thefollowing, equations are obtain, R',R' and RT being the. sameas defined her'ein- IUMULOSIC ACID 5 (1r chloride-and pyrridineinditnethylformamideoto'yieldthe A t -lanostenesf(Compounds 'EE); which are also nevgy v Compounds 'EE are then treated in accordance with dditioi lal" products of this invention. 1

'- Sti11 more final produet's, maybe obtained from the further processing of CompoundsC and Dl-(wherein R' is hydrogen); Instead of further degradation of these compounds'as set forth hereinb'efore they are treated directly toi obtain newfinaljpio'duets'bf this ainuention by-theit" process set forth idth followingequation Theresults described above in the treatment of eburieoic O "OR Res gn) MM NN CVIII R CHaCO;

H300 halide CXV RzCHaCO CXVI R=cnso0; X may be pyrrohdyl, morpholyl or piperidyl.

SS T1 CXVII R CHaCO CXIX R: CHaCO CXVIII R=H CXX R:H 5 CXXI R0: 0

In the first step of the process tumulosic acid is converted to its 3,16-diester derivative (Compounds 'JJ). The 3,16-diester is then converted to a corresponding diester of A -eburicene-ZI-Qic acid (CompoundsKK). Compounds KK are then oxidized to produce the A eburicene -7,11-diones (Compounds LL), which compounds are then reduced to produce the eburicane-7,11- diketo compounds (Compounds MM).- Compounds MM may :be converted to the ll-keto-eburicane compounds (Compounds 00) directly or they may be first converted to-the'dithioethylene ketal derivatives (CompQunds'NN), which compounds may, then be: desulfurized' to produce Compounds 00. Compounds LL, MM, NN and 00 are all new compounds of this invention. v,

Compounds 00 arethen converted into the 2 1-oy1chloproduces the. eburicane-Zl-al-ll-keto compounds '(Compounds QQ) which are new compounds of this invention. Treatment of compounds QQ with asecondary amine, :for example, piperidine, py rrolidine orniorpholine, yields the 'ZI-(N-substituted) eburicanes (Compounds RR) to yield 21-noreburicane-11,20 diketo compounds (Compounds SS). Compounds RR and SS are new compounds of this invention, i

The final tumulosic acid derivatives of this invention are obtained by treatment of Compounds SS with aper: acid and then a base, thus producing compounds TI and UU, both of which are new compounds of this invention. When the ;acyl ester compound is obtained, the ester can be saponified in the usual manner, as by treatment with a base, such as potassium hydroxide to yield the corresponding'ree 'hydroxy derivative, and the fneehydroxy compounds oxidized to the corresponding keto deriva- ;5 tives in the usual manner, as by treatment with-chromium rides (Compounds PP), which are also new compounds of this invention. Hydrogenation of Compounds PP then whichane then. ozonized, and the ozonideformed reduced 3 a oxxrx RECHsCO; RY: -cxxx n='cnsoo; 1

trioxide, to yield Compounds UU..v Additionally, subsequent reduction-of the final compounds, such aszby treatment with lithium borohydride, results in the production of additional new final products of this invention (Compounds UU).

Similarly, as is true in the case of the processing of the derivatives of Eburi-coic Acid, new additional final products ofthis invention are obtained when the derivatives of Tumulosic Acid are likewise processed according to this invention. When the Tumullosic Acid derivative (Compounds JJ are substituted for the Eburicoic Acid derivatives (Compounds A),the results mepresented by the following equations ane obtained, wherein as hemeinbefore defined:

TUMULOSIC ACID DERIVATIVES R, R and R are RO" 7 --0R (l3, i I ROQ on" I V CXLII 11:11; R: (S-meth-Y- R (S-methylhex- 7 hexanoyl) i the -Eburi-coic Acid derivatives, Compounds A. t V

Whenthe Tumulosic Acid 'derijatiViesKCompounds v KKlgai-e (substituted, jfoig' and likewiseytreatedin the same. ;.manner as thefEburicoicxAeid derivatives (Compounds!- B); the-results represented bythe following equations are obtained, whereinR and R'rare aslhereinbefore definedn The processing'of Compounds J J according to thelpro 'cedures set forth above for the processing of Compounds A yields further new products of this'invention, those-be l ing' Compounds VV thIoughfCompounds' DDD,which correspond ital-the products obtained in the treatment of OR OR CLVI R:CHaCO; R':CHa

LLL KKK CLVIII RzCHsCO; R: (4,5 CLXV R: CHuCO; R: (4, dimethylhexanoyl) S-Gimethylhexanoyl) CLIX 3:11; R:(,5- CLXVI RzH; R':(4t,5-

dimethylhexanoyl) dimethylhexanoyl) CLXVII R: R H CLXVIII R :R CHaCO CLXIX ROzO: R: (4,5-

dimethylhexanoyl) CLXX R: 0 H

The processing of Compounds KK' according to the procedures set forth above for the processing of Compounds B yields further new products of this invention, these being Compounds GGG through Compounds LLL, which correspond to the compounds obtained from the treatment of the Eburicoic Acid derivatives, Compounds B.

The treatment of the Tumulosic Acid derivatives (Com pounds KK) according to the procedures set forth above in the processing of the Eburicoic Acid derivatives (Compounds B) to derive Compounds BB and CC, yields further new products of this invention as may be represented by the equations set forth below, wherein R and R ar as hereinbefore defined:

PPP

CLXXII R CHaCO CLXXIII R H CLXXIV R0: 0

The processing of Compounds KK according to the procedures set forth above for the processing of Compounds B to obtain Compounds BB and CC, yields further new products or" this invention, these being Compounds 000 through PPP, which are also new compounds of this invention. 7

Treatment of the Tumulosic Acid derivatives Compounds 00 (wherein R is hydrogen) in accordance with the procedures set forth hereinbefore for the treatment of the Eburicoic Acid derivatives (Compounds F) to obtain the Compounds DD, EE and FF, yields additional products of this invention, as can be represented by the following equations wherein R, R, R" and R' are as hereinbefore defined:

RRR

TTT

CLXXX R=CH3COI onxxxr R=H CLXXXII 110:0:

SSS

CLXXVIII R COHsCO; CLXXIX 125013330; R :H

The processing of Compounds OO-according to the procedures set forth above for obtaining compounds DD, EE and FF, yield new products of this invention, these being Compounds RRR through Compounds TIT.

Treating theTumulosic Acid derivatives LL and MM in accordance with the procedures set forth'hereinbefore' in the treatment of the Eburicoic Acid derivatives Compounds C and Dto obtain Compounds GG and HH, yields further new products of this invention as may be represented by the following equations wherein R, R and R" are as hereinbefore defined:

It on" 1 0R 7 ow -p: Ton

no Mon no won 7 R0 Compounds A are then converted to the corresponding TheProcesslng of Compounds LL a MM P 21 ester of 16a acetoXy-3-keto-A' -eburicadiene-21- to the procedures set forth above for the processing of Die acid (compounds r Compounds 3 are then [Compounds Cand D to obtain compound 66 and duced as by treatment with sodium borohydride and alyields additional new products of this invention, these 59 cohol to ield the 316mb drox 7,9(11) b i di 21..

being Compounds VVV and WWW. oic ,acidSy(ComPo{1;1ds y In addition to the foregoing, when other triterpenoid Com Ound e fh t 1 t d b t t t acids are employed in the process hereinbefore described, p i ace y a e y s men W1 acetlc anhydride in pyridlne at room temper ature to proslightly different results and compounds may be obtained. Thus, when Polyporenic Acid C is employed as the start duce the 3,16-d1acety1-A' -ebur1cad1enes (Compounds ing material, the results represented by the followingrequa- D a tion is obtained, wherein R' and Rare as hereinbefore CGmPOmdS are then Oxidized to Produce the defined: diacetyl A eburicene-7, ll-diketones (Compounds E) POLYPORENIC ACID 0 which are the same compounds as. those produced in the processing of tumulosic acid, to wit (CompoundsLL). ll Compounds E are then processed exactly according to H000 ROOC the procedures set forth for the-subsequent treatment'of Compounds LL to obtain the final products of this invenr 7 tion..

Thus, the processing of PolyporenioAcid C corresponds I l exactlyexcepting the differences noted above to the processing of tumulosic acid and leads to the same correspond- I I i k ing final products. r i Similarly, when triterpenoid acids, such as, elemolic or A I I elemonic acids areemployed in the practice of this inven-n tion, like results are obtained with the exceptionvof the Polyporenic Add 0 A, stereochemical orientation of the 3, 14, 17 and 18 sub- CXCVII R CHsCO stituents.v The results obtained when employing these- 3 CXCVIH' R=CH3CO acids in the practice of this inveniton may be represented at by the following equations (wherein R, R and R" are as hereinbefore defined).

Elemolic Acid Elemolic Acid Derivatives of this Invention R O C iI Thus, when elemolic, elemonic and other like acids are employed as the starting material in the practice of this invention in lieu of eburicoic acid, the final products obtained will possess 3a,14fl,17a,ISa-Substituents rather than the substituents having the stereochemical orientation of the products obtained from the processing of eburicoic, tumulosic, polyporenic and other like acids.

The following examples are illustrative of this invention (all temperatures being in centigrade):

EXAMPLE 1 Acetyl-eburicoz'c acid (I) To a cooled solution of 500 g. of eburicoic acid in 2.37 liters of pyridine 700 ml. of acetic anhydride is added and the mixture allowed to stand overnight at room temperature. The excess acetic anhydride is decomposed by the addition of ice followed by 4 liters of water. The precipitate of crude acetyl-eburicoic acid is collected and dissolved in 4 liters of chloroform. The chloroform solution is washed with hydrochloric acid, water and 5% potassium bicarbonate solution and the solution is then concentrated to two liters. After the addition of 2 liters of methanol, the solution is reconcentrated to a volume of 2 liters and treated with decolorizing charcoal. The solution is then concentrated and 419 g. of the acetyleburicoic acid (I) having a melting point of 240-244, is collected.

EXAMPLE 2 3,16-diacetyl-tumul0sic acid (XC VIII Followingthe procedure of Example 1, but substituting tumulosic acid for the eburicoic acid, 3,16-diacetyl tumulosic acid, M.P. 227-228, (XCVIH) is obtained.

EXAMPLE 3 Acetyl-polyporenic acid C (CXCVIII) Following the procedure of Example 1 but substituting polyporenic acid C for the eburicoic acid, acetyl-polyporenic acid C, M.P., 206-2l0, (CXCVIII) is obtained.

EXAMPLE 4 Methyl-acetyl eburicoate (II) To a suspension of g. of acetyl eburicoic acid (I) in 500 ml. of ether is added a solution of diazomethane EXAMPLE 5 Methyl-3,1 6-diacetyl tumulosate (XCIX) Following the procedure of Example 4 but substituting 3,l-diacetyl-tumulosic acid (XCVIH) for the acetyl eburicoic acid, methyl-3,16-diacetyl tumulosate (XCIX), MP. 159-159.5, is obtained.

EXAMPLE 6 Methyl-acetyl-polyporenare C (CXCVII) Following the procedure of Example 4 but substituting acetyl polyporenic acid C (CXCVIID for acetyl eburicoic acid yields methyl-acetyl-polyporenate' C (CXCVIl),

Nuiol max.

EXAMPLE 7 M ethyl-.i-acetyl-M-eburicene-S fi-ol-Z] -0ate (VII A solution of 85.0 g. of methyl-3-acetyl eburicoate (II) in 1.7 liters of ethyl acetate, absorbs 1 equivalent of hydrogen when shaken in an atmosphere of hydrogen at room temperature and pressure in the presenceof 5.1 g. of Adams catalyst. The catalyst is removed by filtration, the solvent evaporated and the residue is recrystallized from methanol-chloroform to give a first crop of 69.8 g. of methyl S-acetyl A -eburicene-3/3-ol-2l-oate (VII), MP. l56l59, an a second crop of 8.5 g., M.P. 153- 154.

5.78 and 8.02

EXAMPLE 8 M ethyl-3,1 o-diacetyl-A -eburicene- 35,16a-di0l-21-0ate 0111 Following the procedure of Example 7 but substituting methyl-3,16-diacetoxy tumulosate (XCIX) for methyl-3- acetyl eburicoate (II), methyl-3,16-diacetyl-A -3fi,l6otdiol-20-oate, MP. 183-184", (C111) is obtained.

EXAMPLE 9 Metlzyl-16-aceZyl-A -eburicadieneldwol-3-one-2l-oate (CC) Following the procedure of Example 7 but substituting max.

" methyl-acetyl polyporenate (CXCVII) for methyl-acetyl eburico ate, yields methyl-1 6-acetyl-A' -eburicadiene- 16ot-0l-3-0ne-2 1 -oate (CC), MP. 139-141 EXAMPLE 10 M eflzyl-A -eb uricene-Sfi-ol-ZI -0ate (VI) A solution of 500 mg. of methyl-3-acetyl-A -eburicene (3fl-o=l)-2l-oate (Vii) in 200 ml. of l N ethanolic potassium hydroxide is allowed to stand at room temperature for 16 hours. The solution is then neutralized with 20% sulfuric acid and the solids filtered. The filtrate is diluted with water and the ethanol evaporated. The resulting solids are combined with the previously collected material and partitioned between ether and water. The ether layer is washed with Water and evaporated to give 484 mg. of methyl-A -eburicene-3,6-ol-2l-oate (Vl), which is then recrystallized from methanol to yield 284 mg. of crystalline material having a melting point of 139144;

' amass? oate, yieldsf methyl A eburicene-3,8,16adiol-21-oate (CII).

7 EXAMPLE 12 Methyl-A -ebarica'dieae1 oc-l-3-0ne-21-0ate (CCU Following the procedure of Example but substituting methyl -16-acetyl-A' -eburicadiene-l6-ol-3-one-2l-oate (CC) for methyl 3-acetyl A -eburicene-3B-ol-2l-oate, yields methyl -.A -eburicadiene-16a-ol-3-one-21-cate (CCII), MP. 195-197".

EXAMPLE s p A -ebaricen e-3B-0l-21eoic acid (IV) 528 mg. (1 mmole) of methyl-3-acetyl-A -eburicene- 3 6-ol-21-oate.(VII) is dissolved in 20 ml. of collidine' (distilled from potassium hydroxide) containing 870 mg. of lithium iodide (6.5 mole) audthecmixture is heated at reflux under nitrogen for hours. After cooling, the

dark brown mixture is poured into 500 ml. of icedZN hydrochloric acid and extracted iwith ether-methylene chloridesolvent (2 parts ether 1 part methylene chloride). The organic layer is washed with 5% hydrochloric acid and water, dried over sodium sulfate and evaporated to give 518 mg. of A -eburiceue--ol-2l-oic acid (IV). Recrystallization from methanol-chloroform yields a first crop of 162 mg. of (1V), ME, 282-284" anda second crop of 156 mg., M.P. 276-285". a

Following the procedures set forth in Example 13 but substituting methyl 16 acetyl-A eburicadiene16aol-3-one-21-oate (CC) for the methyl-3-acetyl-A -eburi-,

cene-3B-ol-21-oate yields A' -eburicadiene-l6a-ol-3- one-2l-oic acid (CCI).

. EXAMPLE '16 S-acetyl-M-ebaricene-Sfi-oZ-Zl-0ic acid (V) 802 mg. of acetyl eburicoic acid (I) in absolute ethanol absorbs 1 equivalent of hydrogen when shaken in an atmosphere of hydrogen in the presence of 68 mg. of Adams catalyst. Filtration of the catalyst, evaporation of the solvent and recrystallization from methanol-chloroform yields 647 mg. of 3-acetyl-A -eburicene-35-01-21-oic acid (V) having a melting point of 266-268;

Aggy) 5.80, 6.05 1

EXAMPLE 17 3-acelyl-A -ebaricene-3 ($01-21 oic acid (V) Acetylation of 304 mg. of A -eburicene-35-ol-21-oic acid (IV) by acetic anhydride in pyridine at room temperature, yields after recrystallization from methanolchioroform, a first crop of 175 mg. of 3-acetyl-A -eburicene-3fi-ol-21-oic acid (V) melting point about 269-270"; and .a second crop of 130 mg. of (V), MB, 265-2682 as EXAMPLE 18 3,1d-diacetyl-d -ebariceneded6a-diol-21-0ic acid (Ci) Followingthe procedure set forth in Example 16, but substituting 3,16-diacetyl-turnulosic acid (XCVIH) 'for acetyl-eburicoic acid, yields 3,1.6-diacetyl-A -eburicene- 3,8,16 -diol-21-oic acid (CI), MP. 231-2315".

k I EXAMPLE 19 1d-acezyl-A'B -ebaricadiene-I6a-0l-3-0ne-21-0ic 7 acid (CXCIX) Following the procedure set forth in Example 16, but substituting -16-acetyl-polyp0rnic acid (CXCVHI), for acetyl-eburicoic acid, yields 16-acetyl-A -eburicadienel6a-ol-3-onc-2l-oic acid" (CXCK).

EXAMPLE '20 Methyl-3-acetyl-A -ebaricene-3,8-0l-7,1l-dioae V 21-0ate (VIII) A solution of 40 g. of chromic acid in 470' ml. of glacial acetic acid and 30 ml. of water is added to 528g. of methyl-3-acetyl-A -eburicene-Bfl-ol-Zl-oate (VII) in 2.5

liters of glacial acetic acid, .over a period of one hour,

during which the temperature of the mixture is maintained at 75. The temperature'of the mixture is maintained at 75 for an additional hour, at which time the excess chromic acid is decomposed by the addition of 45 m1. of methanol. The reaction mixture is concentrated on the rotary evaporator to approximately 200ml. and after dilution with 400 m1. oiwateris extracted with chloroform. Thechloroform solution iswashed with saturated aqueous sodium chloride, 5% potassium bicarbonate and saturated aqueous sodium chloride and evaporated to dryness. 1 The resultant crude orange semicrystalline product is dissolved in ml. of hexane and 500 ml. of methanol and the solution is concentrated until discernible crystallizationcommences. Orange, impure A -eburicene-7,11- dione (VIII) is collected and redissolved in 200 vn1l.'of benzene. 54 g. neutral alumina is added to the benzene solutionand after swirling for 5 minutes is removed by filtration. ,The alumina is washed with 500 ml. of henzene and the combined filtratesevaporated to yield 26.50 g. of a yellow crystalline material. Recrystallization from methanol gives 19.961 g. of the A -eburicene-7,l1-dione (VIII), MP. 172-173";

To a solution of 5.4 g. of A -eburicadiene-l6-01-3- one-21-oic acid (CCI) in 500 ml. of isopropyl alcohol is added 23 g. of sodium, and the mixture is heated under reflux conditions for 1 hour. After dilution with water, and extraction with ether, 35 g. of A 1 -eburicadiene 3,16adiol-21-oic acid (CCIII) is obtained.

EXAMPLE 23 3-acetyl-M-ebaricene-,8-0l-7,11-di0ne21-0ic aid (IX) Following the procedure set-forth in Example 20, but

substituting 31acety1-A -eburicene-3B-ol-Zl-oic acid '(V) 1 for methyl-3-acetyl-A -eburicene-313-01-2lwoate, yields 3- 3,16-diacetyl-A -eburicene35,16a-v 25 acetyl-A -eburicene-3 3-01-7, 1 1-dione-2 l-oic acid (IX), M.P. 286-288 EXAMPLE 24 3,1 6 -diacelyl-M-eburicene-3 {3,1 6 ot-dil-7,1 1

dione-ZI-oic acid (C V) Following the procedure set forth in Example 20 but substituting 3,16-diacetyl-A -eburicene-3fl;16a-diol-21-oic acid (CI) for methyl 3-acetyl-A -eburicene-3B-ol-2l-oate, yields 3,16 diacetyl-A -eburicene-Iifi,16ot-diol-7,11-dione- 21-oic acid (CV).

EXAMPLE 25 A solution of methyl-3-acetyl-A -eburicene-35-01-7,11- dione-Zl-oate (VIII) in 1.5 liters of glacial acetic acid is heated to reflux and 275 g. of granulated zinc (30 mesh) is added over a period of 15 minutes. After an additional 30 minutes, 75 g. of zinc dust is added. Heating of the mixture is continued until the total reflux time from the start of the first addition equals 60 minutes. The solution is cooled and filtered and the acetic acid is evaporated in vacuo. Recrystallization from methanol-chloroform gives a first crop of 27.13 g. of methyl-3-acetyl-eburicane-3/3-ol- 7,11-dione-2l-oate (XI), MP. l92l93; a second crop of 19.22 g. of XI, MP. 191492; and a third crop of 2.16 g. of XI; M.P. 188-189 EXAMPLE 26 Methyl-3,1 6-diacetyl-ebMfume-36,1 6a-di0l-7,I1 dione-ZI-oate (C VII Following the procedure set forth in Example 25 but substituting methyl 3,16 diacetyl-A -eburicene-3B,16adiol-7,11-dione 21-oate (CIV), for methyl-3-acetyl-A eburicene-3B-7,11-dione 21-oate, yields methyl-3,16-diacetyl-eburicane-3fi,16oc-diol-7,1 1-dione-21-oate (CVII) EXAMPLE 27 Methyl-A' -eburicadiene-3,16ot-di0l-2I-0ate (CV) A solution of methyl-A -eburicadiene-16u-ol-3-one- 21-oate (CCII) in dioxane, is treated with sodium borohydride in aqueous dioxane for one hour at room temperature. Acidification of the mixture with 5% hydrochloric acid and extraction with ether yields a crude product which after recrystallization from methanol-chloroform, gives methyl-A -eburicadiene3,16a-diol-2l-oate (CV).

EXAMPLE 28 Methyl-3,16-diacetyl-A' -eburicadiene-iltiadial-21 -0ate (CC VI Methyl A1901) eburicadiene 3,16zx. diol-21-oate is treated with a solution of acetic anhydride in pyridine containing 2.1 mole equivalents of acetic anhydride at room temperature for eighteen hours. The reagents are evaporated in vacuo and the crystalline residue is recrystallized from methanol. After two crystallizations, methyl-3,16- diacetyl A -eburicadiene-3,16a-diol-21-oate (CCVI) is obtained.

Similarly, following the procedure of Example 28, but substituting A7301) eburicadiene-3,16a-diol-21-oic acid (CCIII) for methyl-A -eburicadiene-3,16a-diol-2loate, yields 3,16-diacetyl-A' -eburicadiene-3,=16a-diol- 21-oic acid (CCIV) EXAMPLE 29 3-acetyl-eburicane-3,B-0l-7,ZI -dione-2I-oic acid (XII) Following the procedure of Example 25 but substituting 3-acetyl-A -eburicene-35-01-7,11-dione-2l-oic acid (IX) for methyl-3-acetyl-A -eburicene-3,8-ol-7,1l-dione-21-oate, yields 3 acetyl eburicane-3,8-ol-7,11-dione-21-oic acid (XII).

26 EXAMPLE 30 Following the procedure set forth in Example 25, but substituting 3,16 diacetyl-A -eburicene-3 ,B,'16ix-diol-7,l1- dione-21-oic acid (CV) for 3-acety1-A -eburicene-318-01- 7,11-dione-21-oic acid, yields 3,16-diacetyl-eburicane-313- 16a-diol-7,11-dione-21-oic acid (CVIII) EXAMPLE 3 1 I p M ethyl-ebzzrz'cane-3/3-ol-7 ,1 1 -dz'0ne-21-0ate (X) A solution of 20 m1. of 1 N ethanolic potassium hydroxide containing mg. of methyl S-acetyl-eubricane-3/3-ol-7,11-dione-2l-oate (XI) is held at room temerature for 14- hours. After neutralization with 20% sulfuric acid, dilution with water and evaporation of the ethanol, the residue is extracted with chloroform and the chloroform solution is washed with water and evaporated. Recrystallization of the crude product from methanol-chloroform yields 20 mg. of methyl-eubricaue- 3fl-ol-7,ll-dione-2l-oate (X), MP. 178479".

EXAMPLE 32 Meflzyl-eburicane-313J 6a-dz'0l-7 ,Z 1 dime-21 -0ate C VI) Following the procedure set forth in Example 31, but substituting methyl 3,16-diacetyl-eburicane-3p,16ct-diol- 7,11-dione-21-oate (CVII), for methyl 3-acetyl-eburicane- 3;3-ol-7,1l-dione-21-oate, yields methyl-eburicane-3B,16cdiol-7,11-dione-21-oate (CV1).

EXAMPLE 33 M ethyl-3,1 o-diacetyl-u -eburicane-3 [3,1 6 cs-diOl-7,1 1

dione-Z] -oate (CI V) Following the procedure set forth in Example 20, but substituting methyl-3 1 6-diacetyl-A -eburicadiene-3,B, 16a-diol-21-oate, obtained in Example 28, for methyl- 3-acetyl-A -eburicene-3/3-ol-2l-oate, yields methyl-3,16-diacety1-A -eburicene-3fi,16u-diol-7,11-di0ne-21-oate (CIV).

EXAMPLE 34 Mefhyl-3-acetyI-7-ethyZenedifhio-eburicane-3B-0l-1I- one-21 -0nte (XIII) 40 ml. of freshly distilled boron triiluoride-etherate is added to a solution of 22.60 g. of methyl-3acetyl eburicane-3;8-ol-7,11-dione-21-oate (XI) and the mixture is held at room temperature for 72 hours. The completely solid mixture is stirred with cold methanol, filtered and Washed with cold 50% aqueous methanol. The dithioethylene ketal (XIII) thus obtained is then dissolved in chloroform, washed with 5% sodium hydroxide and water, dried over magnesium sulfate and the chloroform is evaporated. Recrystallization from methanol-chloroform yields two crops Wei hing 21.63 g., MP. 224-225". The analytical sample of methyl-3-acetyl-7-ethylenedithioeburicane-ll-one-Zl-oate (XIII) (methanol-hexane) has an MP. 227.5-228", [u] +23.9 (chlf. C. 0.48)

Analysis.-Calcd. for C I-I O S C, 68.11; H, 9.21; S, 10.08. Found: C, 67.81; H, 9.13; S, 10.39.

EMMPLE 35 M ezhy l-3,1 6 -diacety l-7-ethy len edi zhi0-eubricane-3 5, 16a-di0l-11-0ne-21-oate (CIX) Following the procedure set forth in Example 34, but substituting methyl-3,l6-diacetyl-eburicane-3fi,16u-diol-7, ll-dione-Zl-oate (CVII), for methyl-3-acetyl-eburicane- 3B-ol-7,11-dione-2l-oate, yields methyl-3,16-diacetyl-7- ethylenedithio eburicane 319,160; diol-l 1-one-21-0ate (CIX).

7 EXAMPLE '36 MethylJ-acelyl eburicane-3[3-ol-l1-one-21-oafe (XIV) A solution of 150 of methyl-3-acetyl-eburicane- 3B-ol-7,1l-dione-Zl-oate- (X1) in 25 m1. of diethylene glycol containing 0.5 ml. of 85% hydrazine hydrate is heated at reflux for 2 hours. After cooling, 3 g. of potassium hydroxidein ml. of. diethylene glycol is added and the temperature of the solution is raised to 195 by distilling off water and hydrazine. The temperature of the solution is maintained at 195 for 4 hours, after which it is cooled... The cooledreaction m xture is poured into 100 ml. of 3 N hydrochloric acid and extracted with ether and chloroform. The combined organic layer is washed with Water, dried over sodium sulfate and Analysis.Calcd. for (3 1-15 0 C, 74.95;. H, 10.36. Found: C, 74.54; H, 10.17.

EXAhdPLE 37 M ethyl-3,1 -diaceiyl-ebu-ricane-j [3,1 6 a-diol-l 1 -one- 7 ZI-oate (CX) Following the procedure set forth in Example 36, but substituting methyl-3 ,1d-diacetyl-eburicane-3/3,16ot-diol-7,

rated. The aqueous suspension is then extracted with ether and the other solution washed withwater, dried over magnesium sulfate and evaporated. Recrysta1lization from methanol yields 1.55 g. of methyl-eburicaneifiol-l l-one-Zl-oate (XV), Ml. 13 3-13 5. The analytical sample melts at 137-139;

Analysis.-Calcd. for (3 E 0; C, 76.44; H,'10.83. FoundfC, 76.14; H, 10.63.

EXAMPLE 41 M ethyl-eburicane-j 6,1 6 e-diol-I Lone-21 -0ate (CXI Following the procedure set forth in Example 40, but. substituting methyl- 3,16 diacetyl eburicane 35,167

diol-ll-one-Zl-oate (CX), for methyl-S-acetyl-eburicane- 3,9-01-1 l-onc-21 -oate, yields methyl-eburicane-3fi,l6a-diol- 1l-one-21-oate (CXI) EXAMPLE '42- 11-dione21-oate (CV11), for methyl-3-acetyl-eburicaneol 7,11-dione21-oate, yields methyl-3,16-diacetyleburicane-3,8,16a-diol-1l-oire-Zl-oate (CX').

EXAMPLE 38 M ethyl-3-acezyl-ebtgricanfifl-ol-Z 1 -0ne -21 -0ate (XIV) 360 cc. of sponge nickel catalyst is Washed with absolute ethanol andadded to asolution of 10.0 g. of methyl-3- acetyl-7-etl1ylenedithio-3/5'-ol-11-one-21-oate (XIlI) in 1.5

liters of absolute ethanol and the mixture is heated at reflux for 16 hours. The catalyst is tilt red and washed with alcohol and acetone. The combined filtrates are evaporated, the residue dissolved in chloroform and the Following the procedure set'forth in Example 38, but substituting methyl 3,16-diacetyl-7-ethylenedi-thio-eburicane 3fi,16c diol-l l-one-21-oate (CIX) for methyl-3- acetyl 7 ethylenedithio-eburicane-3B-ol-11-one-21-oate, yields methyl-3 ,16-diacetyl-eburicane-3B,16a-diol-1 l-one- 21-oate (CX).

EXAMPLE, 40

Methyl-eburicane-3fl-0l-J 1 -0ne-21 -oate .(X V) A solution of 2.0 g. of methyl-3-acetyl-eburicane-3fl-olll-one-Zl-oate (XIV) in 400 ml. of 1 N ethanolic potassium hydroxide is allowedto stand at room temperaturev for 18 hours. The solution is then neutralized with 20% sulfuric acid, diluted with Water and the ethanol evapo- .i-acetyl-eburicmz-e-3f3-0l-J 1 -0ne-21 mic-acid (XVI) 554 mg. (1 mmole) of methyl-3-acetyl-eburicane-3g3- ol-ll-one-Zl-oate (XiV) is demethylated by refluxing in 20 ml. of collidine distilled over potassiumhydroxide,

containing 870mg. of lithium iodide (6.6 mmole) under nitrogen for 15 hours. The cooled dark brown reaction mixture is poured into 500.ml. of iced 2 N-hydrochloric acid and extracted With etheru'nethylene chloride. The organic layer is Washed with 2 N hydrochloric acid and Water, dried over magnesium sulfate and evaporated to dryness. The product is reacetylated by treatment with pyridine-acetic anhydride at room temperature and is allowed to stand overnight. Recrystallization of the reacetylated material from methanol-chloroform'yields a first crop of 251 mg. of .S-acetyl-eburicane- 3,8-ol-l 1-one-2l-oic acid (XVI), MP. 284286; and a second crop of 83 mg, MP. 283284. The analytical sample has the, following properties: MP. 286287;

Analysis.-Calcd. for C H O C, 74.67; H, 10.26.. Found: C, 74.37; H, 9.56.

EXAMPLE 43 3,16-diaceiyZ-eburicane-3p,1 owdiol-l 1 -0ne-21,-oic acid (CXII Following the procedure set forth in Example 42, but substituting methyl 3,16 diacetyl eburicane 35,160- diol-ll-one-Zl-oate (CX), for methyl-3-acetyl-eburicane- 3,8-ol-l1-one-2l-oate, yields 3,16-diacetyl-ehuricane-3fi, l6a-diol-11-one-2I-oic acid (CXII).

, EXAMPLE 44 Eburicane-Sfi-ol-IZ-one-21-0ic acid (XVII) ond crop of 167 mg., Ml. 288:291".

max. -89; 6-00}! EXAMPLE. 45 Eburicane-3,8,1 6oz-di0Z-l Lone-21 -0ic acid (CXIII) "Followingthe procedure set forth in Example 44 but substituting 3,16 diacetyl eouricane 33,160 diol l1- 29 one-21-oic acid (CXII) for 3-acetyl-eburicane-3B-ol-11- one 21-oic acid yields eburicane-3,B,l6a-diol-l1-one-21-oic acid (CXILI).

EXAMPLE 46 3-acetyl-A -lanstene-3p-0l-24-0ne-21-0ic acid (XXX) Through a solution of 15 g. of acetyl-eburicoic acid (I) in a mixture of 150 ml. of chloroform and lSO ml. of ethyl acetate, cooled in a Dry Ice-acetone bath, is passed 26.2 liters of ozone (1 mole of ozone contained in 0.89 liter of oxygen). The resulting solution is allowed to warm to room temperature and then added to a suspension of 975 mg. of pre-reduced palladium on charcoal catalyst in 50 ml. of ethyl acetate. 550 ml. of hydrogen is taken up rapidly, following which the solution is filtered and the filtrate evaporated to dryness in vacuo to yield 3-acetyl-A -lan0stene-3B-ol-24-one- 21-oic acid (XXIX).

EXAMPLE 47 3,16a-diacetyl-A -lanestate-3,8,16ot-di0l-24-0ne-2I-0ic acid Following the procedure set forth in Example 46 but substituting 3,16-diacetyl-tumulosic acid (XCVlII), for

acetyl-eburicoic acid yields 3,16a-diacetyl-A -lanostene 3,3,16a-diol-24-one-2l-oic acid (CXXVII).

EXAMPLE 48 M thyl-3-acetyl -A -lanostene-3 fi-ol-24-0ne-21 oate (X XXI A solution of 310 mg. of 3-acetyl-A -lanostene-3,B-ol- 24-0ne-21-oic acid (XXX) in either, is methylated by treatment with diazomethane in ether. Two recrystallizations from methanol-chloroform yields pure methyl-3- acetyl-A -lanostene-3fl-ol-24-one-2'1-oate (XXXI), M.P. 173-174"; [a] +5l.6 (chlf. C, 0.63);

REE; 5.76-5.78, 5.83 (sh), 8.05;;

Analysis.-Calcd. for C H O C, 72.82; H, 10.06. Found: C, 72.80; H, 9.85.

EXAMPLE 49 M ethyl-3,1 6 -diacetyl-A -lanostene-S [3,1 6 a-di0l-24-0ne- 21-0ate Following the procedure set forth in Example 48, but substituting 3,16 diacetyl A lanostene 33,160: diol- 24-one-2l-oic acid (CXXVH) for 3-acetyl-A -lanostene- 3fi-ol-24-one-2l-oic acid yields methyl-3,16-diacetyl-A lanostene-Zifi, 1605-(1101-24-01'16-21-0Eti6 (CXXVIII) EXAMPLE 50 Methyl-3-acetyl-A -lan0stene-3,8-0l-7,11,24-tri0ne- 21-06116 (XXXII) A solution of 5.5 g. of methyl acetyl eburicoate (Ii) in 450 ml. of glacial acetic acid is ozonized at room temperature. The reaction mixture is diluted with Water and the precipitate solids are collected and dried in vacuo. The ozonolysis product is dissolved in 400 ml. of glacial acetic acid, warmed to 70 and oxidized by the dropwise addition of 6.6 g. of chromic acid in 100 ml. of 90% acetic acid over a period of 40 minutes. The solution is stirred magnetically and the temperature maintained at 70 for an additional hour and is then left to stand overnight at room temperature. Excess chromic acid is destroyed by the addition of methanol, and the resultant green solution is poured into 5 liters of'water. Extraction with ether and Washing of the ether solution with 5% sodium bicarbonate and water, drying the resultant solution over sodium sulfate and evaporation of the solvent yields 3.25 g. of yellow semicrystalline material. Chromatography on 150 g. of acid Washed alumina gives in benzene-ether eluates, 800 mg.

-of yellow crystalline methyl-3-acetyl-A -lanostene-isfi-ol- 7,11,24-trione-21-oate (XXXIII). Recrystallization from an methanol yields a first crop of 300 mg. of XXXII, M.P. 194-195 (softening at 192);

max.

(e=8,700); and a second crop of 150 mg. of (XXXII), M.P. 186188;

Methyl-3,16-diacetyl-A -lan0steize-3,B,16a-di0l- 7,11,24-trz'one-21-oate (CX X IX Following the procedure set forth in Example 50, but substituting methyl-diacetylwtumulosate (XCIX) for methyl-acetyl-eburicoate yields methyl-3,16-diacetyl-A lanostene-35,16a-diol-7,1 1,24-trione-21-oate (CXXIX) EXAMPLE 5 2 M ethyl-3 -acetyl-A -lan0stene-3 ,B-0l-7,1 1,24-tri0ne- 21-0ate (XXXII) To a solution of 87 mg. of methyl-3-acetyl-A -lanostene- 3fi-ol-24-one-21-oate (XXXI) in 8 ml. of glacial acetic acid at 70 is added 98 mg. of chromic acid in 2 ml. of 90% acetic acid. The solution is held at 70 for an additional hour and is left to stand overnight at room temperature after which methanol is added to decompose the excess chromic acid. Water is added to the reaction mixture which is concentrated to 10 ml. in the rotary evaporator, diluted to 25 ml. with water and extracted with ethyl acetate. The ethyl acetate solution is washed with 5% potassium bicarbonate and Water, dried over sodium sulfate and evaporated to mg. of yellow oily material. Chromatography on 7 g. of neutral alumina gives 29 mg. of yellow crystalline material in the henzene-chloroform fractions. Recrystallizations from methanol yields 14 mg. of methyl-3-acetyl-A lanostene-3,B-ol- 7,11,24-trio11e-21-0ate ()QQGI), M.P. 189-192".

EXAMPLE 5 3 Methyl-3,l6-diacetyl-A -lanosten12-313,] dot-diol- 7,11,24-tri0nc ZZ-Oate (CXXIX) Following the procedure set forth in Example 52 but substituting methyl 3,16 diacetyl-A -lanostene-3{3,16adiol-24-one-21-oate (CXXVIH) for methy1-3-acetyl-A lanostene-3 3-ol-24-one-2l-oate yields methyl 3,16-diaoetyl-A -lanostene 35,160; diol 7,11,24 trione 21-oate (CXXIX).

EXAMPLE 5 4 Methyl-3-acetyl-lanostane-B-ol-Z]1,244tri0ne- 21-0ate (XXXIV) 7 To a refluxing solution of 207 mg. of methyl-3-acetyl- A -lanostene-3 3-ol-7,ll,24trione-21-oate (XXXII) in 15 -ml. of glacial acetic acid is added 1.24 g. of zinc dust over a period of 5 minutes. The yellow color of the solution is discharged after 10 minutes and heating is continued for an additional 30 minutes. The reaction mixture is cooled, filtered from zinc and zinc acetate, evaporated to dryness in vacuo, and the resulting residue dissolved in ethyl acetate. The solution is then Washed with water, dried over sodium sulfate and evaporated to yield 198 mg. of white crystalline material. Recrystallization from methanol-methylene chloride yields a first crop of 169 mg. of methyl-3-acetyl-lanostane-35-01- 7,11,-24-trione-2l-oate (XXXIV), M.P. 243.5-245 and a second crop of 21 mg. of (XXXIV), MP. 240241.5. The analytical sample from a methanol recrystallization has the following physical properties: M.P. 244-245"; [04 +50.4 (chlf. C, 1.10);

max.

Found: c, 70.96; H, 9.05.

31 EXAMPLE 55 Methyl-3,1 6-diacetyl-lanostane 35,1 6a-dz'ol-7,11,24 trioneZ l-oate (CXXXI') Following the procedure set forth in Example 54 but substituting methyl 3,16 diacetyl A -lanostene-3B,16a-

diol-7,l1,24-trione-21-oate acid (CXXIX) for methyl-3- acetyl-M-lanostene-3fl-ol-7,11,24.-trione 21 oate yields methyl-3,16-diacetyl lanostane 3&160; diol 7,11,24- trione-Zl-oate (CXXXI). v V 7 EXAMPLE 5 6 Followingthe-procedure set forth in Example 52 but substituting 3-acetyl-A -lanostene-3,B-ol-24-one-2l-oic acid (XXX) for methyl-3-acetyl-A -lanostene-3fi-ol-24-one-2L oate, 3 acetyl A 1anostene-3 eel-7,1 1,24-trione-21-oic acid (XXXIH) is obtained.

EXAMPLE s7.

3,16-diacetyl-A -lanostene-flfi,16a-dil-7,11,24-

trione 21-'0ic acid (CXXX) Following the procedure .set forth in Example 52 but substituting 3,16-diacetyl-A -lanostene-3,8,16a-diol-24-one- 21-oic acid (CXXVII) for methyl-3-acetyl-A5-lanostene- 3 3-ol-24-one-21-oate yields 3,16 diacetyl Mdanostene- 3F ,16a-dlOl-7,1 1,24-1Ii0116-21-01C acid (CHX) EXAMPLE 58 3-acetyl-lanostane-3 ,8-0l-7 ,1 1 ,24-tri0ne-21 -0ic acid (XXX V) Following .the procedure of Example 54, but substituting 3-acetyl-A -lanostene-3fl-ol-7,11,24-trione-21-oic acid (XXXIII) for methyl-3-acetyl-A -lanostene-3 {3-01-11 1,2 trione-Zl-oate, 3 ElCBWldfillOSfEEIifi-F:,B-0l-7,11,24-l11'l0I1fi-21- oic acid (XXXV) is obtained.

EXAMPLE 59 3,1 6-diacetyl-lan0stane-3p3,1 6a-di0l -7,1 1,24- ri0ne- 21-0ic acid (CXXXII) Following the procedure set forth in Example 54 but substituting 3,16diacetyl-A danistene-3 ,8,16 z-diol-7,1 1,24- trione-Zl-oic acid (CXXX) for methyl-S-acetyl-M-l-anos tene-3fi,16a-diol-7,11,24-tri0ne-21-oate 'yields 3,16-diacetyl-1anostane-3fl,16e.- diol 7,11,24 trione 21 oic acid (CXXXII).

EXAMPLE 60 M ethyl-.i-acetyl-24-ethylenedithio-lanostane-S 8-01- 7,11-a'ione-2I-0ate (XXX VII To a solution of 139 mg. of methyl-3-acetyl-lanostane- 35-01-111,24 trione-2Loate ()G(X1V) in ml. of ethanedithiol is added 5 ml. of freshly distilled boron-trifiuorideetherate. After being allowed to stand for 30 minutes at roomtemperature, thereaction mixtureis poured into,

ice-water. The organic layer is separated and the aqueous layer isextracted with ether. The-combined organic lay ers are evaporated and dried under high vacuum. The solid residue is recrystallized from methanol-methylene chloride to. give 60 mg. of sulfur containing material,

M.P. 260-270. Repeated recrystallization of the impure product from methanol-methylene chloride yields 13 mg. of the methyl-3-acetyl-24-ethylenedithioJanostane-3fl-ol-7,1l-dione-Zl-oate (XXXVII) having the following ;physical properties: M.P. 251-252";

Analysis.-Calcd. for C H O S C, 66.22; H, 8.59; S, 10.08. Found; C, 66.37; H.883; $311.71.

\ Nuiol "max.

EXAMPLE 61 M ethy 1-3,] 6-diacetyl-24 -ethyle1zedi thioelanostane- 3,8,16a-di0l-7,11-di0ne-21-0ate (CXXX V) Following the procedure set forth in Example but substituting methyl-3,16-di2tcetyl-lanostane 3 ,B,-16c-diol- 7,11,24-trione-21-oate (CXVII) for methyl-3-acetyl-l-anostane-Efl-ol-Zl1,24-trione-2l-oate yields methyl-3,16-diacetyl 24-rethylene-dithio-lanostanc-3,8,16a-diol-7,1l'dione-21-oate (CXX).

EXAMPLE 62 3-acetyl-24-ethylenedithio-Zanostane-3l3-0ZJ,1 I dione-ZJ -0ic acid Following the procedure of Example 60, but substituting 3-acetyl-lanostane 35-01-7,l1-24-trione-21-oic acid (XXXV) for methyl-3-acetyl-lanostane-3fl-ol-7,11,24-trione-Zl-oate, yields 3-acetyl-24-ethylenedithio-lanostane- 3/3-0l-7,11-dione-21-oic acid.-

EXAMPLE '63 3,1 6-diacetyl-24 -ethylenedithi 0-lan0stane-3 5,1 6 ocdi0l-7,1 1 -di0ne-21-0ic acid (CXXXVI) Following the procedure set forth in Example 60 but substituting 3,16 diacetyllanostane-3fi,16a-diol-7,11-24- trione-Zl-oic acid (CXXXH) for -n1ethyl-3-acetyl-lanostane-Sfi-ol-Zl1,24-trione-21-oate yields 3,16-diacetyl-24 ethylenedithio-lanostane-3,B,16a-diol-7,l1-dione 21 oic acid (CXXXVDV EXAMPLE 64 39 rag. of impure methyl-3-acetyl-24-ethylenedithiolanostane- 3/i-ol-7,ll-dione-Zl-oate (XXXVII) in 25 ml. of

acetone with 2 g. of Rauey nick-e1 is heated under reflux for 12 hours. solvent evaporated to yield 27 ing. of crystalline material. Two successive recrystallizations from methanol yields methyl-3-acetyl-lanostane-35-ol-7,1 l-dione-Zl-oate (XL) having the following properties: M.P. 193194;

xggf 5.75 and 5.83;;

Analysis.- -Calcd. for 0 151 0 0, 72.75; H, 9.62. Found: 0, 72.72; H, 9.31.

EXAMFLE Methyl-3,16-diacetyl-lan0szane-3BJ6a-di0l-7,11- dione-Zl -0ate (CXXXIX) Following the procedure set forth in Example 64, but

substituting methyl-3,16-diacetyl-24-ethylenedithio lano- Following the procedure set forth in Example 64 but substituting 3,16-diaoetyl-24 ethy1enedithi0-lanostane-3B-- lfioc-diOl-Zl1-dl011e-21-0i0 acid (CXXXVI) for methyl-3- acetyl-24-ethylenedithio-lanostanza-3B-ol-7,1l-dione 21 oate yields 3,16-diacetyl-lanostane-3fi,16u-diol-7,11-dione- 21-oic acid (CXL).

The nickel is removed by filtration and the 33 EXAMPLE 68 M ethyl-3-acetyl-7 ,24-bis-ethylenedithio-lanostane-3/3- l-] 1 -0ne-21 -0ate (XXXVI) A solution of 236 mg. of methyl-3-acetyl-lanostane-3,B- ol-7,11,24-trione-21-oate (XXXIV) in 0.8 ml. of ethane- .dithiol and 1.0 ml. of freshly distilled boron trifiuorideerties: M.P. 271-272 (sinters at 267).

Analysis.-Calcd. for C H O S C, 62.42; H, 8.28; S, 18.01. Found: C, 61.88; H, 8.27; S, 18.52.

EXAMPLE 69 M ethyl-3,1 6-diacetyl-7,24bis-ethylenedithio-lanostane- 318,1 6a-di0l-1 1 -0ne-21-0ate CX X XIII Following the procedure set forth in Example 68, but substituting methyl-3,16-diacetyl-lanostane 3 3,160: diol- 7,11,24-trione-21-oate (CXXXI) for methyl-3-acetyl-lanostane-Ilfi-ol-Zl1,24-t1ione-21-oate yields methy1-3,16-diacetyl-7,24-bis-ethylenedithio-lanostane 3;3,16adiol-11- one-21-oate (CXXXIII).

EXAMPLE 70 3 -acetyl-7,24-bis-ethylcnedithi0-lan0stane-3/3-0I-1 I one-21 -0ic acid Following the procedures of Example 68, but substituting 3-acetyl-lanostane-3B-ol-7,11,24-trione 21 oic acid (XXXV) for methyl-3-acetyl-lanostane-3;8-ol-7,'11,24-trione-Zl-oate yields 3-acetyl-7,24-bis-ethylenedithio -lanostane-3B-ol-1l-one-Zl-oic acid.

EXAMPLE 71 3,16-diacetyl-7,24-bis-ethylenedithio-lanostane- 3,8,1 6a-di0l-1 1-0ne-21-0ic acid (CX XX I V) Following the procedure set forth in Example 68, but substituting 3,16'diacetyl lanostane-3B,16a-dio1 7,11,24- trione-21-oic acid (CXXXII), for methyl-S-acetyl-lanostane-3fi-ol-7,11-24-trione-21-oate yields 3,16-diacetyl- 7,24-bis-ethylenedithio lanostane-3B,16oc-diol-1 1-one-2 1- oic acid (CXXXIV).

EXAMPLE 72 M ethyl-3-acetyl-lan0stane-3 fi-ol-I I -0ne-21 -0ate (X X X VIII A solution of 22 mg. of the bis-thioketal (XXXVI) in 50 ml. of absolute ethanol is refluxed overnight with Raney nickel. The Raney nickel is then removedby filtration and the solvent is evaporated. The residue, on recrystallization from methanol gives mg. of methyl- 3-acetyl-lanostane-3fi-ol-l1-0ne-21-oate (XXXVIH) having the following properties: M.P. 177178;

[a] I-54.7 (chlf. C, 0.53); A231? 5.75, 5.89, 8.01 i EXAMPLE 73 M ethyl-3,1 6 -diacetyl-lan0stane-3 3,1 6 oc-diOl-l 1- one-ZI-oate (CXXXVII) Following the procedure set forth in Example 72, but substituting 3,16 diacetyl-7,24-bis-ethylenedithio lanostane-3B,16a-diol-1l-one-21-oate (CXXXIII) for methyl- 3 acetyl 7,24-bis-ethylenedithio-3fi-ol-11-one-21-oate yields methyl-3,16-diacetyl-lanostane-Sfi,16a-diol-ll-one- 21-oate (CXXXVII).

34 EXAMPLE 74 3-acetyl-lanostane-SB-ol-l1-0ne-21-oic acid (XXXIX) '16ot-dio1-1 1-one-21-oic acid (CXXXVIII) EXAMPLE 76 M ethyl-3-acetyl-lanostarw-3fi-ol-J 1 -one- 21-0ate (X X X VIII A solution of 215 mg. of methyl-3-acetyl-lanostaxle-3B- 0l-7,11,24-trione-21-oate (XXXIV) in 30 ml. of diethylene glycol containing 3 g. of potassium hydroxide and 1 ml. of hydrazine hydrate is heated at reflux for 30 minutes. The temperature of the mixture is then raised to 195 by the distillation of water and hydrazine, and held at 195 for two hours. The solution after cooling, is poured into ml. of 3% hydrochloric acid and is extracted with chloroform. Evaporation of the chloroform leaves a residue of 163 mg. which when reacetylated by treatment with pyridine and acetic anhydride and then remethylated by treatment with ethereal diazomethane, yields 187 mg. of crude methyl-3-acetyl-lanostane-3B-ol- 11-one-21-oate (XXXVIH) which is chromatographed on 15 g. of neutral alumina. Evaporation of the benzenechloroform eluate yields 74 mg. of material, which after two recrystallizations from methanol gives 21 mg. of XXXVIII having an M.P. of about 172174.5. The analytical sample melts at 178179.5 and has the following properties:

Nuiot EXAMPLE 77 M ethyl-3,16-diacetyl-lan0stane-3 5,1 6 Ot-diOl- 11-0ne-21-0ate (CXXXVII) Following the procedure set forth in Example 76, but substituting methyl-3,16-diacetyl-lanostane-3fl,16a diol- 7,11,24-trione-21-oate (CXXXI) for methyl-3-acetyllanostane-3 8-ol-7,11,24-trione-21-oate yields methyl-3,16- diacetyl lanostane 3,8,16oc diol 11 one 21 oate (CXXXVII).

EXAMPLE 78 Methyl-3-acetyl-eburicane-3 6,1 1 fi-diol- 2I-0ate (LXX VII A solution of 100 mg. of methyl-3-acetyl-eburicane-3tiol-11-one-21-oate (XIV) in 10 ml. of dry tetrahydrofuran is added to 200 mg. of lithium borohydride in 15 ml. of tetrahydrofuran and is left at room temperature for 2 hours. The excess lithium borohydride is decomposed by the addition of 10 m1. of 10% aqueous acetic acid. The tetrahydrofuran is evaporated, the residue extracted with ether and the ether solution Washed with water and evaporated. Three recrystallizations from methanol yields 39 mg. of analytically pure methyl-3-acetyl-eburicane-3B,l1fi-diol-21-oate (LXXVII) having the following properties: M.P. 203.5-204"; [0:1 +54.8 (chlf. C, 2.07);

Analysis.Calcd. for C H O C, 74.68; H, 10.69; OCH 5.67. Found: C, 74.64; H, 10.21; OCH 5.01.

Similarly, treating methyl-3-acetyl-lanostane-3/S'-ol-11- EXAMPLE 80 a 3-acetyl-eburicane-36J.Ifl-diol-ZI-oic acid (LXXVI Following the procedure set forth in Example 78, but

substituting 3-acetyl-ebu'ricane-3 9-ol-11-one-21-oic acid (XVI) for methyl-3-acetyl-eburicane-3,8-ol-1l-one-Zloate, yields B-acet l-ebuIicane-BBJI fidio121-oic acid (LXXVI).

Similarly,- treating 3-acetyl-lanostane-3;B-ol-11-one 2loic acid according to the procedure set forthin Example 78,.yields 3-acetyl-lanostane-3BJlfi-diol-Zl-oic acid.

EXAMPLE 81 3,1 6-diacetyl-eburicane-3BJ16,16e-triol- 21-0ic acia (CLXXV) Following the procedure set forth in Example 78 but substituting 3,16 diacetyl-eburicane-3fl,16e-diol-1l-one- 21-oic acid .(CXII) for methyl-3-acetyl-eburitiane-3B-ol- 11-one-2 l-oate yields 3,l6-diacetyl-eburicane-3 3,11,8,16utriol-Zl-oic acid (CLXXV).

EXAMPLE 82 Methyl-eburicane-3BJ1 fi-diol-Zl-oate (LX X VIII A. solution of 109 mg. of methy1-eburicane-3 3-ol-1 1- one-Zl-oate (XV) in ml. of tetrahydrofuran is added dropwise to 113 mg. of lithium borohydride in 10 ml. of tetrahydrofuran and held at room temperature for two hours. The excess lithium bo-rohydride is decomposed by the addition of 10% aqueous acetic acid. The tetrahydrofuran is evaporated, the residue extracted with chloroform and the chloroform solution washed with water and evaporated. The crude product is. then recrystallized from methanol three times to yield mg. of crudeproduct having a melting point of '180.5183. One further recrystallization from methanol yields 19 mgLofrnethyl eburicane 36,11 3 diol 21 oate (LXXVIII) having the following properties: M.P. 186- 188; 1.

Analysis.Calcd. for C H O C, 76.14; H, 11.18; OCH 6.12. Found: C, 76.12; H, 11.35; OCH 6. 26.

EXAMPLE 83 M ethyl-eburicane-Et [3,1 1 [1,1 6a-trz'ol-21 -0izte CLXX VII Following the procedure set forth in Example 82, but substituting methyl-eburicane 35,1611 dio1-11-one-21- oate (CX'I) for methyl eburicane-Bfi-ol-l1-one-21 oate yields methyl-eburicane 35,115,160 triol- 21 oate (CLXXVII).

EXAMPLE 84 Methyl-3-acetyl -A D-eburicanedB-ol-ZI-0ate (LXXIX layer is washed with water, dried over magnesium sulfate.

and evaporated. Recrystallization of the crude'product from methanol yields 8 mg. of analytically pure methyl- 689 3-acetyl-A -eburicne-SB-ol-Zl-oate (LXXIX) having the following propertiesLMP. 154-155 [0:] 62.0 (chit. C, 0.66); and a second crop of 4 mg. of (LXXIX) having a M.P. -152".

,kfiii." 5.81, 8.05;. Analysis.--Calcd. for (3341153071 C, H, 10.67. Found: C, 77.52; H, 10.93.

Similarly, treating methyl-3-acetyl-lanostane-3B,11 3- diol-21-oate according to the procedure of'Example 84, yields .methyl-3-acetyl-A -lanostene-3 8-ol-2l-oate.

EXAMPLE s5 Following the procedure set-forthin Example 84, but substituting methyl 3,16 diacetyl-eburicane 3,8,1113, 16oc-t110i-21-021t6 (CLXXVI) for .methyl-3-acety1-eburicane 35,1113 diol 21 oate yields methyl 3,16 diacetyl-A -eburicene-3B,1-6a-diol-21-oate (CLXXVIII) EXAMPLE 86 3-acetyL-A -eburicene-fli-ol-Zl-0ic acid (LXXX).

Following the procedure set forth in Example 84 but substituting 3 acetyl eburicane 35,115 diol 21' oic acid (LXXVI) for methyl-3-acetyl-eburicane-3,B,1lfl-diol- 21-oate, yields 3-acetyl-A -eburicene-3/3-ol-21-oic acid (LXXX).

Similarly, treating '3-acety1-1anostane-3B, 1 lfi-diol-Zl-oic acid, according to the procedure set forth in Example 84, yields 3-acetyl-A -lanostene-3p ol-2l-oic acid.

EXAMPLE 87 3,16-diacetyl-A -eburicene-3fi,16a-ol-2l-0ic acid (CLXXIX) Following the procedure set forth in Example 84 but substituting 3,16 diacetyl-eburicane 36,116,160; trio]- 21-oic acid (CLXXV) for methyl-3-acetyl-eburicane-3 8, llfl-diol-Zl-oate yields 3,16-diacetyl-A -eburicene-3fi, 16a-ol-21-oic acid (CLXXIX).

EXAMPLE 88 Methyl-3-acetyl-A -eburicene-3fi-0l-7-0ne-2J-0ate (LV) A solution of mg. of chromic acid in 3.5 ml. of glacial acetic acid is added to 337 mg. of methyl-3-acetyl- A -eburicene-3fi-ol-21-oate (VII) in 15 ml. of glacial acetic acid and held for five days at room temperature. The excess chromic acid is decomposed with methanol and the solution evaporated on the rotary evaporator. The residue is partitioned. between ethyl acetate and water. The organic layer is washed with 5% potassium carbonate, and water, driedover sodium sulfate and evaporated. The residue is chromatographed on 15 g.

of neutral alumina and eluted with benzene and benzenechloroform to yield a white crystalline material which on recrystallization from methanol gives 14 mg. of methyl- 3 acetyl A eburicene 3 3 ol 7 one 21 oate, M.P. 161-1625".

Additional quantities of methyl-3-acetyl-A -eburicene- 3,6-ol-7-one-21-oate (LV) are obtained from the chromatography of the mother liquors of the zinc dust reduction of methyl 3 acetyl- A eburicene 3,8 ol 7,11-

dione-Zl-oate (VIII) obtained in Example 20. Recrys- PM 252 mp. (e -8,400); i335; 5.81, 5.99

max.

Analysis.Calcd. for C I-1 0 C, 75.23; H, 10.03;; Found: C, 75.11; H, 10.33.

3? EXAMPLE 89 M ethyl-3,1 6-diacetyl-A -eburicene-3,B,16a-diol-7- one-21 -aze (CLV) Following the procedure set forth in Example 88 but substituting methyl 3,16 diacetyl A eburicene 3,8, 16a-diol-21-oate (0111) for methyl-3-acetyl-A -eburicene- 3,3-ol-21-oate yields methyl-3,16-diacetyl-A -eburicene-3B, 16a-diol-7-one-21-oate (CLV).

EXAMPLE 90 3-acetyl-A -eburicene-3fl-0l-7-0ne-21mic-acid Following the procedure of Example 88 but substituting 3 acetyl A eburicene 3d ol 21 oic acid (V) for methyl 3 acetyl A eburicene 3B ol 21 oate, yields 3-acetyl-A -eburicene3B-ol-7-one-2l-oic acid.

EXAMPLE 91 3,1 6-diacetyl-A -eburicene-3 [3,1 6 u-di0Z-7-0ne-2I -0ic acid Following the procedure set forth in Example 88 but substituting 3,16 diacetyl A eburicene 35,160: diol- 21-oic acid (XCI) for methyl-3-acetyl-A -eburicene-3B-ol- 21-oate yields 3,16-diacetyl-A -eburicene-3fl,16a-diol-7- one-2l-oic acid.

EXAMPLE 92 M ethyl-3-acetyl-eburicane-3 S-ol'J-one-Zl -0ate (L VI) A solution of 100 mg. of 3-acetyl-A -eburicene-35-ol-7- one-Zl-oate (LV) in 20 m1. of absolute ether is added to 25 ml. of liquid ammonia over a 5-minute period. At the same time, 75 mg. of lithium wire, cut into small pieces, is added so as to maintain the blue color of the solution. After 15 minutes, ml. of ether-tert.-buty1 alcohol is added and the ammonia is permitted to evaporate. The solution is then diluted with an additional 10 ml. of ether and washed with water. Evaporation of the ether yields 98 mg. of the crude product. Chromatography on 4 g. of neutral alumina and elution with benzene-chloroform yields 25 mg. of methyl-3-acetyleburicane-3B-ol-7-one-2l-oate (LVI) after recrystallization from methanol.

EXAMPLE 93 Methyl-3,1 6-diacetyl-eburican e313,] 6a-diol-7- one-2.1 -0ate (CL VI) Following the procedure set forth in Example 92 but substituting 3,16 diacetyl A eburicene 313,16u diol- 7-one-2l-oate (CLV), for 3-acetyl-A -eburicene-35-01-7- one 21 oate, yields 3,16 diacetyl-eburicane 3 3,161:- diol-7-one-2l-oate (CLVI).

EXAMPLE 94 3-acetyl-eburicane-3-0l-7-one-2J-0ic acid (LVII) Following the procedure set forth in Example 92 but substituting 3 acetyl A eburicene 318 ol 7 one- 2l-oic acid obtained in Example 90, for 3-acetyl-A eburicene-3fl-ol-7-one-2l-oate, yields 3-acetyl-eburicane- 3B-ol-7-one-2l-oic acid (LVII).

EXAMPLE 95 3,1 6-diacelyl-eburicane-3 8,1 6 a-a'z'ol-7-0ne- ZI-OI'C acid (CLVII) Following the procedure set forth in Example 92, but substituting 3,16-diacetyl-A -eburicene-3 8,16a-diol-7-one- 2l-oic acid obtained in Example 91, for B-aCetyl-A -eburicene 3 3 ol 7 one 21 oate, yields 3,16 diacetyleburicane-Sfl,16a-diol-7-one-21-oic acid (CLVII) EXAMPLE 96 M ethyl-3-acetyl-7-ethylenedithio-eburicane-3 13-02-21 -0ate Following the procedure set forth in Example 35, but substituting methyl 3 acetyl eburicane-3B-ol-7-one-21- oate (LVI) for methyl-3-acetyl-eburicane-3 8-ol-7,1l-dione-21-oate, yields methyl-3-acetyl-7-ethylenedithio-eburicane-Sfl-ol-Zl-oate.

EXAMPLE 97 Methyl-3,16-a'iacetyl-7-ethylenedilhio-eburicane- 3 3,1 6a-di0l-21 -0ate Following the procedure set forth in Example 34 but substituting methyl-3 16-diacetyl-eburicane-3fi, 16a-di01-7- one-21-oate (CLVI), for methyl-3-acetyl-eburicane-3,B-ol- 7,1l-dione-21-oate, yields methyl-3,16diacetyl-7-ethylenedithio-eburicane-3fi,16a-diol-21-oate.

EXAMPLE 98 M ethyl-3 -acetyl-eburicane-3 5-01-21 -oate Following the procedure set forth in Example 38, but substituting methyl 3 acetyl-7-ethylenedithio-eburicane- 3fl-ol-21-oate, obtained in Example 96, for methyl-3-acetyl 7 ethylenedithio eburicane 3 p3 ol-11-one-21-oate. yields methyl-3-acetyl-eburicane-3fi-ol-21-oate.

EXAMPLE 99 Methyl-3,16-diacetyl-eburicane-3;8,I6a-di0l-21-0ate Following the procedures set forth in Example 38, but substituting methyl 3,16-diacetyl-7-ethylenedithio-eburicane-3/3,l6u-diol-2l-oate, obtained in Example 97, for methyl 3-acetyl-7-ethylenedithio-eburicane-3B-ol-1l-one- 21-oate, yields methyl-3,16-diacetyl-eburicane-3,B,16tz-diol- 21-oate.

EXAMPLE 100 3-acetyl-eburicane-Sfi-ol-I 1 -0ne-2I -oyl chloride (XVIII) Analysis-(Saki for C H O Cl: C, 72.20; H, 9.66; Cl, 6.46. Found: C, 72.46; H, 9.74; Cl, 6.5.

Similarly, substituting thionyl bromide in the treatment of 3-acetyl-eburicane-3,B-ol-11-one-21-oic acid for the thionyl chloride employed in the procedure of Example 100, yields 3 acetyl eburicane-3B-ol-11-one-21-oyl bromide (XVIII).

EXAMPLE 101 3,1 6-dz'acetyl-eburicane-3 [3,1 6a-a'i0l-1 1 -0ne-21-oylchloride (CXI V) Following the procedure set forth in Example 100, but

- substituting 3,16 diacetyl-eburicane-3fi,16a-diol-1l-one- 21-oic acid (CXII) for 3-acetyl-eburicane-3B-ol-1l-one- 2l-oic acid yields 3,16-diacetyl-eburicane-3fi,16a-diol-1lone-21-oyl chloride (CXIV).

EXAMPLE 102 3-acetyl-M-eburiceneJB-ol-ZI-0yl chloride (LXXI) A solution of 6.56 g. of 3-acetyl-A -eburicene-3B-ol-Z1- oic acid (V) and 20.4 ml. of thionyl chloride in 200 ml. of benzene is heated at reflux for 4 /2 hours. The solvent and excess thionyl chloride is removed by distillation under reduced pressure, and the residue is dried under high vacuum over potassium hydroxide for 18 :hours. Recrystallization from acetone yields a first crop of 1.57 g. of 3-acetyl-A eburicene-3 3-ol-21-oyl chlorid (LXII), M.P. 174-175; and a second crop of 3.36 g. of LXII, M.P. 172-174;

Nuiol max.

39 Similarly, substituting thionyl bromide for thionyl chlo-v ride in the. procedure set'forth in Example 102 for the treatment of 3-acetyl-A-eburicene-3{3-01-2l-oic acid (V), yields 3-acetyl-A-eburicene-3fl-ol-2l-oyl-brornide.

EXAMPLE 103 3,1o-diacetyl-A -eburicene-3B,16a-di0l-21-0yl-chl0ride (CLXXI) Following the procedure set forth in Example 102, but Substituting 3,16-diacetyl-A -eburicene-3B,16e-di0l-2l-0ic acid (CI). for 3-acetyl-A -eburicene-3fl-ol-2l-oic acid, yields 3,16 diacetoxy A eburicene-3 ,B,160t-diO1-21-0y1 chloride, (CLXXI).

EXAMPLE 104 3-acetyl-eburicane-SB-ol-l Lone-21 -oyl-chlriae (XVIII) A solution of 4.4 g. of 3-acetyl-eburicane-3,6-ol-1l-one- 21-oic acid (XVI) in 30 ml. of thionyl chloride is held at for 16 /2 hours. After evaporation of the thionyl chloride under reduced pressure at room temperature and drying the residue under high vacuum, crude 3-acetyl-eburicane-Bfi-ol-l1-one-2l-oyl-chloride (XVIII) is obtained. Recrystallization from acetone-hexane yields a first crop of 3.79 g, of XVIII, M.P. 2l5217; and a second crop of 334 mg. of XVIII, M.P. 210-212.

Following the procedures set forth in Example 100*, but

(LXXX) for 3-acetyl-eburicane-3,8 o1-11-one-21-oic acid, yields 3-acetyl-A -eburicene-3 ,8-ol-21-oyl chloride.

Similarly, treating 3-acety1-A lanostene-3B-ol-2l-oic acid according to the procedure set forth in Example 100,

substituting 3,l6-diacetyl-lanostane-3B,l6a-diol-1l-one-Zloic acid (CXXXVIII), for 3-acetyl-eburicane-35-01-11- one-21-oic acid yields 3,1o-diacetyl-lanostane-3/3,1Get-diol- 11-one-21-oyl chloride.

' EXAMPLE 108 V 3-acetyl-lanostane-3/3-ol-7J1-dione-21-0yl chloride Following the procedure set forth in Example 100, but substituting 3 acetyl lanostane3B-ol-7,11-dione-21-oic acid (XLI) for B-acetyl-eburicane-SB-ol-11-one-21-oic acid, yields 3 acetyl lanostane-Tafi-ol-Zl1-dione-2l-oyl chloride. a

7 EXAMPLE 109 3,16-diacetyl-lanostane-SBJ 6u-diol-7,11-di0ne-21-0yl chloride Following the procedure set forth in Example 100, but substituting 3,16 diacetyl lanostane-3 fi,16ec-dlO1-7,1 l-di- 0ne-2l-oic acid (CXL), for 3-acetyl-eburicane-3{3:01-11- one-21-oic acid, yields 3,16-diacetyl-lanostane-3[3,16e diol-7,11-dione-21-oyl chloride.

EXAMPLE 110 3-acelyl-A -eburicene-3[3-ol-2l-oyl chloride Following the procedure set forth in Example 100, but substituting 3-acetyl-A -eburicene-3 ,8 01- 21 oic acid yields 3-acetyl-A -lanostene-3 ,B-ol-21-oyl chloride.

' EXAMPLE 1 1 1 3,16-diaeetyl-A -ehuricene-dfll6oi di0l-21-0yl chloride Following the procedure of Example 100, but substituting 3,16-diacetyl-A -eburicene-3 3,164 diol 21 oic acid (CLXXIX) for 3-acetyl-eburicanee3fl-ol-1Lone-21- oic acid yields 3,16-diacetyl-A -eburicene-3l3,loot-diol- 21-oyl chloride.

EXAMPLE 112 I d-zzcetyl-M-eburicene-Sfl-ol-7,1J-diOne-ZLoyZ chloride Following the procedure set forth in ExamplelOO, but substituting 3-acetyl-A -eburicene-3{3-01-7,1l-dione-Zl-oic acid (IX) for 3-acetyl-eburicane-3p-ol-11-one-21-oic.acid yields 3-acety1 A -eburicene-35-01-7,ll-dione-Zl-oyl chloride.

' EXAMPLE 113 7 3,1 o-diacetyl-A -eburicene-fiflJ 6 oi-diol-7 ,1 I -dz'0ne-21 -oyl chloride Following the procedure set forth in Example 100, but substituting 3 ,1 6-diacetyl-A -eburicene:B,16a-dio1-7,1 l-dione-Zl-oic acid (CV) for 3-acetyl-eburicane-3e-ol-1l-one- 21-oic acid yields 3,16-diacetyl-A -eburicene-3[3,16a-diol- 7,11-dione-2l-oyl chloride.

EXAMPLE 114 3-acetyl-eburicane-3/3-0l-7,1l-dione-ZI-oyl chloride Following the procedures set forth in Example 100, but substituting 3-acetyl-eburicane-3/3-ol-7,1l-dione-Zl-oic acid (XII) for. 3-acetyl-eburicane-3p-ol-l1-one-21-oic acid, yields 3 acetyl-eburicane-3,8-ol-7,11-dione-21-oyl chloride.

EXAMPLE 115 Following the procedure set forth in Example 100, but substituting 3,16 diacetyl eburicane-3 B,16c-dlO1-7,1 l-dione-21-oic acid (CVIII) for 3-acetyl-eburicane-3[3-ol-11- one-Zl-oic acid 7 yields 3,16-diacetyl-eburicane-3/3,16adiol-7,1l-dione-21-oyl chloride.

EXAMPLE 116 3-acetyl-ebziricarze-3 8-ol-21-0ic acid Following the procedure set forth in Example 42 but substituting methyl-3-acetyl-eburicane-Zifi-ol-Zl-oate, obtained in Example 98, for methyl-3-acetyl-eburicane-3,B- ol-11-one-2'1-oate yields 3-acetyl-eburicane-3[3-01-2l-oic acid.

EXAMPLE 117 S-acetyl-buricane-Sfl-ol-Zl-oyl chloride Following the procedures setforth in Example 100, but substituting 3-acetyl-eburicane-3fi-ol-2l-oic acid obtained in Example 116, for 3-acetyl-eburicane-3fl-ol-l1-one-21- oic acid, yields 3-acetyl-eburicane-3fl-ol-2l-oyl chloride.

EXAMPLE 118 V 3,16-diacetyl-ebWichita-3B,]6ot-di0l-21-oie acid Following the procedure set forth in Example 42, but substituting methyl 3,16-diacetyl-eburicane-3B,l6a-diol- 21-oate, obtained in Example 99, for methyl-3-acetyleburicane-3/3-ol-11-one-21-oate, yields 3,16-diacetyl-eburicane-3B,l6a-diol-2l-oic acid. i

' EXAMPLE 119 3,16-diacetyl' buricane-SQJ6e-diol-2Z-0yl chloride Following the procedure set forth in Example 100, but 

1. METHYL-3-ACETYL-7-ETHYLENEDITHIO-EBURICAN-3B/OL-11ONE-21-OATE.
 12. A STEROID SELECTED FROM THE GROUP CONSISTING OF 3-ACETYL - 21 - (N-PYRROLIDYL)-$20-EBURICENE-3B-OL-11-ONE; 3-ACETYL - 21 - (N-PIPERIDYL)-$20-EBURICENE-3B-OL-11-ONE; AND 3-ACETYL - 21-(N-MORPHOLYL) - $20 - EBURICENE-3B-OL11-ONE. 